2. Academic Validation
  3. Delineating the role of cooperativity in the design of potent PROTACs for BTK

Delineating the role of cooperativity in the design of potent PROTACs for BTK

  • Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):E7285-E7292. doi: 10.1073/pnas.1803662115.
Adelajda Zorba 1 2,  Chuong Nguyen 2,  Yingrong Xu 2,  Jeremy Starr 2,  Kris Borzilleri 2,  James Smith 2,  Hongyao Zhu 3,  Kathleen A Farley 2,  WeiDong Ding 2,  James Schiemer 2,  Xidong Feng 2,  Jeanne S Chang 2,  Daniel P Uccello 2,  Jennifer A Young 2,  Carmen N Garcia-Irrizary 2,  Lara Czabaniuk 2,  Brandon Schuff 2,  Robert Oliver 2,  Justin Montgomery 2,  Matthew M Hayward 2,  Jotham Coe 2,  Jinshan Chen 2,  Mark Niosi 4,  Suman Luthra 5,  Jaymin C Shah 5,  Ayman El-Kattan 4,  Xiayang Qiu 2,  Graham M West 2,  Mark C Noe 2,  Veerabahu Shanmugasundaram 2,  Adam M Gilbert 2,  Matthew F Brown 2,  Matthew F Calabrese 6
Affiliations

Affiliations

  • 1 Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139.
  • 2 Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340.
  • 3 Computational Sciences, Medicinal Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340.
  • 4 Medicine Design, Pfizer Worldwide Research and Development, Groton, CT 06340.
  • 5 Pharmaceutical Sciences Small Molecule, Pfizer Worldwide Research and Development, Cambridge, MA 02139.
  • 6 Discovery Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340; matthew.calabrese@pfizer.com.
PMID: 30012605 DOI: 10.1073/pnas.1803662115
Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 Ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (Btk), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with Btk and Cereblon (CRBN, an E3 Ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo Btk degradation. Our data show that alleviation of steric clashes between Btk and CRBN by modulating PROTAC linker length within this chemical series allows potent Btk degradation in the absence of thermodynamic cooperativity.

Keywords

BTK; PROTAC; catalytic; proteasome; targeted protein degradation.

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